Malaria causes a high rate of mortality, especially in children in tropical countries. This situation has been exacerbated with the emergence and spread of multiple drug-resistant malaria and insecticide- resistance in the vector. Thus, there is a need for intensive research in vaccine development, but first, one needs to know what constitutes naturally acquired immunity. This study is designed to determine when an infant first becomes infected, and then compares the immune response of the infant before and after infection. The longitudinal study will involve 100 newborn infants who will be followed form 0-12 months of age and their blood and serum samples analyzed every other month. Peripheral blood will also be drawn from the mothers at parturition. All serum samples will be screened for antibodies recognizing candidate asexual- and sexual-stage vaccine antigens (MSP-1, MSA-2, Pfs25, AMA-1 Pfs27, Pfs230, and Pfs48/45) by immunoprecipitation and ELISA assays. The immune responses will be correlated with HLA type to determine whether HLA effects the specificity and /or rate of development of protective immunity. Parasite DNA from the red blood cells will be isolated and used to determine if parasites are present, as well as to evaluate parasite diversity. Species diversity will be tested using species- specific oligonucleotide primer pairs to amplify sequences present in the small subunit ribosomal RNA (ssRNA genes of P. falciparum, P. malariae and P. ovale. Identification of the different Plasmodium species by this technique (as opposed to microscopy of blood slides) has the advantage of being more sensitive and accurate; therefore, mixed infections will be easily detectable. Genetic diversity of P. falciparum will be evaluated by restriction fragment length polymorphism (RFLP) analysis using 23 RFLP markers which identify all 14 nuclear chromosomes of P. falciparum. Most of these 23 RFLP probes encode P. falciparum proteins which have been implicated in parasite growth, cytoadherence, immune evasion and drug resistance. Correlation of the serological and genetic diversity data will help in understanding the acquisition of natural immunity to malaria in infants.